ledipasvir and Liver-Neoplasms

BACKGROUND Hepatitis C virus (HCV) genotype 4 (GT-4) is widespread in the Middle East, where it is responsible for the majority of HCV infections. It shows moderate treatment response rates when compared to other genotypes in the current era of interferon-based regimens. However, in the era of direct acting antiviral (DAA) drugs, its response is at least as good as observed for HCV genotypes 1-3. CASE REPORT We present a case of a 44-year-old patient with HCV cirrhosis. Since 2007, he has been treated for HCV infection with multiple ineffective regimens of interferon (INF) and ribavirin. A liver biopsy in 2010 revealed stage 5-6/6 indicating cirrhosis, which was later complicated by the occurrence of portal vein thrombosis and a large hepatocellular carcinoma (HCC) (maximum diameter 9 cm). The patient was successfully treated with sorafenib, transcatheter arterial chemoembolization (TACE), and radiofrequency ablation. After four TACE procedures, the patient's AFP (alpha-fetoprotein) decreased remarkably and almost normalized. The HCC disappeared radiologically as shown by triple phase CT, MRI with contrast, and PET-CT. He successfully underwent a living donor liver transplantation. Four weeks post liver transplantation he started treatment with sorafenib, and switched from tacrolimus to Rapamune (sirolimus) as immunosuppressant therapy. Ten weeks after liver transplantation, HCV treatment was introduced along with ledipasvir and sofosbuvir due to his increasing liver enzyme levels. A rapid viral response was achieved after 14 days. In total, the patient received 12 weeks of this treatment. CONCLUSIONS This case study might be of significance in informing early management and personalized treatment of patients with recurrent HCV GT-4 infections after liver transplantation, even in complex clinical surroundings.

Topics: Antiviral Agents; Benzimidazoles; Carcinoma, Hepatocellular; Drug Therapy, Combination; Fluorenes; Hepatitis C, Chronic; Humans; Liver Neoplasms; Liver Transplantation; Living Donors; Male; Middle Aged; Sofosbuvir

Chronic hepatitis C, without treatment, can cause liver cirrhosis, liver failure and liver cancer. The availability of new oral direct acting antivirals, such as the protease inhibitors simeprevir, asunaprevir and paritaprevir, the NS5A inhibitors daclatasvir, ledipasvir, and ombitasvir, the polymerase inhibitors Sofosbuvir and dasabuvir have resulted an enormous progress in the treatment of chronic hepatitis C, leading to >90% sustained viral response rates. Even the hard-to-treat or previously treatment ineligible patients can be cured with the combination of these drugs. Furthermore the treatment duration is much shorter, and the side effects are minimal. Today, treatment of all hepatitis C virus infected patients is recommended, and the best choices are the interferon-free options. Eradication of hepatitis C virus has become realistic, however, appropriate screening programs are mandatory to achieve this goal.

Topics: 2-Naphthylamine; Administration, Oral; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Clinical Trials as Topic; Cyclopropanes; Drug Therapy, Combination; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 3-Ring; Humans; Imidazoles; Interferons; Isoquinolines; Lactams, Macrocyclic; Liver Neoplasms; Macrocyclic Compounds; Nucleic Acid Synthesis Inhibitors; Proline; Protease Inhibitors; Pyrrolidines; Simeprevir; Sofosbuvir; Sulfonamides; Uracil; Uridine Monophosphate; Valine; Viral Load; Viral Nonstructural Proteins; Virus Replication

Many herbal medicines are effective anti-inflammatory agents and may therefore suppress the development of hepatocellular carcinoma (HCC). Recently, treatment with a single-tablet regimen containing ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with hepatitis C virus genotype 1 infection who did not respond to prior interferon-based treatment. Patients with chronic hepatitis C are expected to receive this treatment worldwide. However, many patients have hepatitis-like fatty liver and nonalcoholic steatohepatitis. A strategy to prevent the development of HCC in this subgroup of patients is urgently required. Whether herbal medicines can suppress the development of HCC remains to be established. However, herbal medicines are effective anti-inflammatory agents and may inhibit the development of HCC. Clinical trials exploring the effectiveness of herbal medicines in the prevention and treatment of HCC are therefore warranted. The current lack of knowledge and of educational programs is a barrier to increasing the use of potentially effective herbal medicines and performing prospective clinical trials.

Topics: Animals; Anti-Inflammatory Agents; Benzimidazoles; Carcinoma, Hepatocellular; Clinical Trials as Topic; Cysteine; Drug Combinations; Drugs, Chinese Herbal; Fatty Liver; Fluorenes; Glycine; Glycyrrhetinic Acid; Glycyrrhizic Acid; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Phytotherapy; Plant Preparations; Sofosbuvir; Tablets

The course of hepatitis C disease has changed with the use of direct-acting antiviral drugs in the treatment of the disease. The aim of this study was to evaluate the real-life efficacy and safety of the sofosbuvir/ledipasvir drug regimen in the treatment of patients with genotype 1b.. Treatment-naive or -experienced 49 genotypes 1b patients treated with sofosbuvir/ledipasvir participated in the study. Laboratory and hepatitis C virus RNA values were evaluated at baseline, week 12, and week 24 of treatment (36th week for those who received 24 weeks of treatment).. The sustained virologic response rate was 100% in patients who completed treatment. At the end of the study, there was a significant decrease in alanine transaminase, aspartate transaminase, gamma-glutamyl transferase, and alpha-fetoprotein levels (P = .000014, P = .000581, P = .000012, and P = .000821), respectively. Renal function tests (creatinine, estimated glomerular filtration rate) worsened (P = .003 and P = .007, respectively). Hepatocellular carcinoma (HCC) was developed in 2 patients during post-treatment follow-up. In Kaplan-Meier analysis, the probability of not developing HCC was 86.5% at 26 months.. The sofosbuvir/ledipasvir combination is effective in treating genotype 1b chronic hepatitis C with high sustained virologic response rates. Because there are few drug interactions, it may be a suitable option for patients taking multiple medications or who are transplant recipients. Renal function should be monitored closely during and after treatment, as there is a risk of worsening renal function after treatment.

Topics: Antiviral Agents; Benzimidazoles; Carcinoma, Hepatocellular; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Neoplasms; Sofosbuvir; Sustained Virologic Response; Treatment Outcome

As patients with chronic hepatitis C virus (HCV) tend to be older and/or have advanced liver disease in Japan, real-world data are needed to evaluate safe and effective treatment options. The study aim was to assess safety and effectiveness of ledipasvir/sofosbuvir (LDV/SOF) in a real-world cohort of Japanese patients with HCV genotype (GT) 1 infection overall and by patient subgroups: elderly, compensated cirrhotic, advanced fibrotic and those with hepatocellular carcinoma (HCC). A large prospective observational study was conducted, enrolling adult patients treated for HCV GT1 infection with LDV/SOF at clinical sites across Japan. Patients were observed for safety outcomes during and 4 weeks after treatment, and for sustained virologic response at 12-weeks post-treatment (SVR12). Incidence rates (IRs) of adverse drug reactions (ADRs) and serious ADRs (SADRs) and SVR12 rates were assessed overall and by subgroups. ADR and SADR IRs were low (2.26 and 0.17 per 100 person-months, respectively) and did not significantly differ in elderly patients or those with presence of compensated cirrhosis, worsening fibrosis or HCC. SVR12 rates were high overall (98.5%) and across subgroups investigated (≥94%), including patients who were elderly (98.2%), treatment-experienced (97.6%), advanced fibrotic (≥95.8%), had existing NS5A resistance-associated substitutions reported pre-treatment (95.0%), compensated cirrhosis (95.7%), HCC (94.0%) and other chronic liver diseases (96.1%). In this large, real-world observational study of Japanese patients with HCV GT1 infection, LDV/SOF treatment resulted in low incidence of adverse events, with high real-world effectiveness, even among patients with potentially higher risks of adverse safety outcomes and treatment failure.

Topics: Adult; Aged; Antiviral Agents; Benzimidazoles; Carcinoma, Hepatocellular; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Japan; Liver Neoplasms; Sofosbuvir; Sustained Virologic Response

Data are sparse on treatment of chronic hepatitis C virus (HCV) in cancer patients. We evaluated the efficacy and safety of sofosbuvir-based therapy (SOFBT) in cancer patients.. Patients treated with SOFBT at our center during 2014-2017 were included in a prospective observational study. Efficacy [sustained virologic response at 12 weeks after the end of treatment (SVR12)], cancer-related outcomes and adverse events (AEs) were assessed.. We included 153 patients. Most were men (109; 71%), white (92; 60%), non-cirrhotic (105; 69%), and with HCV genotype 1 (110; 72%). The most common cancers were hepatocellular carcinoma (HCC) (27; 18%) and multiple myeloma (14; 9%). The overall SVR12 rate was 91% (128/141). SVR12 was 100% in patients treated with ledipasvir/sofosbuvir for 8 weeks. Of the 32 patients initially excluded from cancer clinical trials because of HCV, 27 (84%) were granted cancer therapy access after starting SOFBT. Six patients with indolent non-Hodgkin's lymphoma (NHL) received SOFBT without cancer treatment. Two achieved complete remission, one had partial remission, and two had stable cancer. Within 6 months after SOFBT, 5% (6/121) of patients in remission or with stable cancer, had progression or recurrence (two with HCC and one each with esophageal cancer, cholangiocarcinoma, NHL, and tonsillar cancer). No de novo HCCs occurred. AEs were most commonly grade 1-2 (90%).. SOFBT in HCV-infected cancer patients is effective and safe, may permit access to investigational cancer therapy expanding treatment options, may induce remission of NHL, and may be used for 8 weeks.

Topics: Aged; Antiviral Agents; Benzimidazoles; Breast Neoplasms; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Fluorenes; Head and Neck Neoplasms; Hepatitis C, Chronic; Heterocyclic Compounds, 4 or More Rings; Humans; Imidazoles; Interferons; Liver Neoplasms; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Neoplasms; Polyethylene Glycols; Prospective Studies; Pyrrolidines; Ribavirin; Simeprevir; Sofosbuvir; Sustained Virologic Response; Valine

Recently, a controversy has emerged: is the rate of recurrence of hepatocellular carcinoma (HCC) higher following treatment of hepatitis C virus (HCV) with direct-acting antiviral (DAA) therapy? However, the risk of HCC recurrence has not been studied in liver transplant (LTx) recipients who received DAA therapy. The aim of the present study is to compare the rate of HCC recurrence in LTx recipients who did or did not receive DAA therapy.. Sixty-three patients received LTx with HCC. Twenty-seven (42.9%) with HCV received DAA therapy (Group A), 20 (31.7%) with HCV did not receive DAA therapy (Group B), and 16 (25.4%) did not have HCV (Group C).. In group A, three (11%), in group B, one (5%), and in group C, none had recurrence of HCC. Actuarial 4-year recurrence-free survival was 88.9, 95, and 100% in group A, B, and C, respectively (p = 0.37). Group A was subdivided into two groups for comparison with Group B: A1 included five patients who had end of treatment response (ETR) without sustained virological response (SVR), and A2 included 20 patients who achieved SVR. Three patients from A1 had HCC recurrence and no patients from A2 had HCC recurrence. (p = 0.0038; group A1, A2, and B).. The rate of HCC recurrence in LTx patients with DAA therapy was significantly higher with ETR, without SVR, after DAA therapy compared to patients with SVR or patients who did not receive DAA therapy. LTx recipients with HCC receiving DAA therapy requires further studies.

Topics: Aged; Antiviral Agents; Benzimidazoles; Carcinoma, Hepatocellular; Disease-Free Survival; Drug Therapy, Combination; Female; Fluorenes; Hepatitis C, Chronic; Humans; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Ribavirin; Simeprevir; Sofosbuvir; Sustained Virologic Response

Excellent efficacy and safety profile of second-generation DAA combinations improved treatment of chronic hepatitis C (HCV) as well as in HCV recurrence after orthotopic liver transplantation (OLT). The need of ribavirin addition is under debate as anaemia and decreased renal function are prevalent in transplant cohorts. The aim of this study was thus to assess safety and long-term efficacy of RBV-free DAA combinations in HCV-recurrent patients after OLT.. A total of 62 OLT recipients (male: 50%/81%; age: 60.7 ± 8.5 years [mean ± SD]; GT - 1: 48, GT - 3: 9, GT - 4: 5; cirrhosis: 34%/55% [7%/21% decompensated], fibrosing cholestatic hepatitis: 1%/2%) received RBV-free treatment with second-generation DAA combinations: sofosbuvir (SOF)/daclatasvir (DCV): 42%/68%, SOF/simeprevir (SMV): 10%/16%, SOF/ledipasvir (LDV): 6%/10% and PrOD: 4%/7%.. Data of at least 96 weeks of FUP after treatment cessation (mean: 120; up to 167 weeks) were analysed. All patients showed on-treatment response. By intention-to-treat (ITT) analysis, SVR12 was 97% (60/62, GT-1a: 11/11 [100%]; 1b: 33/34 [97%]; 1g: 1/1 [100%]; subtype not specified: 2/2 [100%]; GT3a: 9/9 [100%]; GT4: 4/5 [80%]) compared to SVR96 of 89% (55/62). No late relapses occurred. In total, 16 severe adverse events occurred, including two newly diagnosed carcinoma (lung cancer, hepatocellular carcinoma). Six patients died; one at treatment week 24 (HCV-RNA undetectable) and five during treatment-free FUP and after achieving SVR (SVR4: N = 1, SVR12: N = 3, after SVR96: N = 1 respectively). Reasons for death were: multi-organ failure (N = 4), impaired graft function (N = 1) and unknown (N = 1).. RBV-free DAA combinations for the treatment of HCV recurrence after OLT are highly efficacious and well tolerated. Our long-term data show that viral eradication is durable but not necessarily translated into beneficial long-term clinical outcome.

Topics: Aged; Antiviral Agents; Austria; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Fluorenes; Follow-Up Studies; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Pyrrolidines; Recurrence; Ribavirin; Simeprevir; Sofosbuvir; Sustained Virologic Response; Valine

We aimed to describe the real-world efficacy and safety of combination therapy with ledipasvir and sofosbuvir (LDV/SOF) for chronic hepatitis C virus (HCV) genotype 1 (GT1) infection.. This retrospective analysis of a prospective, nationwide, multicenter registry included GT1-infected patients treated with LDV/SOF for 12 weeks. We assessed the rate of sustained virological response at 12 weeks post-treatment (SVR12), incidence of adverse events, and serum markers of hepatocellular carcinoma (HCC).. Among the 1461 patients included (mean age, 69 years; 29.5% aged > 75 years; cirrhosis, 23.8%; history of treatment for HCC, 10.9%), the overall SVR12 rate was 98.4% (1438/1461). Factors associated with treatment failure were cirrhosis (odds ratio, 4.19; p = 0.014) and resistance-associated substitutions (RASs) in NS5A at baseline (odds ratio, 7.78; p = 0.0004). The SVR12 rate in patients with cirrhosis and NS5A RASs was 93.0% compared to 100% in patients without cirrhosis or NS5A RASs. In patients with SVR, the levels of alpha-fetoprotein (AFP), AFP-L3, and Mac-2 binding protein glycosylation isomer (M2BPGi) decreased from baseline to end of treatment (from 13.4 ± 37.6 to 6.0 ± 10.6 ng/mL, p < 0.0001; from 2.2 ± 4.9 to 1.5 ± 6.3%, p < 0.005; and from 3.6 ± 3.7 to 2.0 ± 3.5 cut-off index, p < 0.0001; respectively). Adverse events were rare and not associated with age. No decrease in estimated glomerular filtration rate was observed in patients with baseline chronic kidney disease stage 3.. LDV/SOF therapy is highly effective and safe in elderly Japanese patients with HCV GT1, even in the presence of cirrhosis or NS5A RASs. Patients with SVR may have a lower risk of HCC.

Topics: Adult; Aged; Aged, 80 and over; alpha-Fetoproteins; Antiviral Agents; Benzimidazoles; Carcinoma, Hepatocellular; Drug Therapy, Combination; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Japan; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies; Red Cross; Retrospective Studies; Risk; Sofosbuvir; Sustained Virologic Response; Treatment Failure; Viral Nonstructural Proteins; Young Adult

This study compared the cost-effectiveness of direct-acting antiviral therapies currently recommended for treating genotypes (GT) 1 and 4 chronic hepatitis C (CHC) patients in the US.. A cost-effectiveness analysis of treatments for CHC from a US payer's perspective over a lifelong time horizon was performed. A Markov model based on the natural history of CHC was used for a population that included treatment-naïve and -experienced patients. Treatment alternatives considered for GT1 included ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (3D ± R), sofosbuvir + ledipasvir (SOF/LDV), sofosbuvir + simeprevir (SOF + SMV), simeprevir + pegylated interferon/ribavirin (SMV + PR) and no treatment (NT). For GT4 treatments, ombitasvir/paritaprevir/ritonavir + ribavirin (2D + R), SOF/LDV and NT were compared. Transition probabilities, utilities and costs were obtained from published literature. Outcomes included rates of compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC) and liver-related death (LrD), total costs, life-years and quality-adjusted life-years (QALYs). Costs and QALYs were used to calculate incremental cost-effectiveness ratios.. In GT1 patients, 3D ± R and SOF-containing regimens have similar long-term outcomes; 3D ± R had the lowest lifetime risks of all liver disease outcomes: CC = 30.2%, DCC = 5.0 %, HCC = 6.8%, LT = 1.9% and LrD = 9.2%. In GT1 patients, 3D ± R had the lowest cost and the highest QALYs. As a result, 3D ± R dominated these treatment options. In GT4 patients, 2D + R had lower rates of liver morbidity and mortality, lower cost and more QALYs than SOF/LDV and NT.. While the results are based on input values, which were obtained from a variety of heterogeneous sources-including clinical trials, the findings were robust across a plausible range of input values, as demonstrated in probabilistic sensitivity analyses.. Among currently recommended treatments for GT1 and GT4 in the US, 3D ± R (for GT1) and 2D + R (for GT4) have a favorable cost-effectiveness profile.

Topics: 2-Naphthylamine; Adult; Aged; Aged, 80 and over; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Cyclopropanes; Drug Therapy, Combination; Female; Fibrosis; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Neoplasms; Macrocyclic Compounds; Male; Markov Chains; Middle Aged; Models, Econometric; Proline; Quality-Adjusted Life Years; Ribavirin; Simeprevir; Sofosbuvir; Sulfonamides; Uracil; Valine

New treatments for chronic hepatitis C virus (HCV) are highly effective in patients coinfected with human immunodeficiency virus (HIV). This study estimated the cost-effectiveness of treatments for genotype 1 (GT1) HCV in HIV-coinfected patients.. A Markov model based on HCV natural history was used. The base-case analysis included both treatment-naïve and -experienced patients. Alternatives were ombitasvir/paritaprevir/ritonavir, dasabuvir with or without ribavirin (3D ± R) for 12 or 24 weeks, sofosbuvir plus peginterferon and R (SOF + PR) for 12 weeks, SOF + R for 24 weeks, and no treatment (NT). A subgroup analysis restricted to treatment-naïve, non-cirrhotic patients compared 3D ± R for 12 weeks to SOF plus ledipasvir (LDV) for 12 weeks and NT. Transition probabilities, utilities, and costs were obtained from the published literature. Outcomes were measured over a lifetime horizon and included rates of compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver-related death, total costs, life-years, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER).. In the base-case, SOF + R was dominated by both SOF + PR and 3D ± R. Compared to SOF + PR, 3D ± R had an ICER of $45,581. The lifetime rates of liver morbidity and mortality were lower among those treated with 3D ± R compared to SOF + PR, SOF + R, or NT. In the subgroup analysis, 3D ± R was cost-effective compared to NT at a threshold of $50,000 per QALY (ICER $27,496). SOF/LDV had an ICER of $104,489 per QALY gained compared to 3D ± R.. In the GT1 HCV population coinfected with HIV, 3D ± R was cost-effective compared to NT, SOF + R, and SOF + PR. In the treatment-naïve sub-population, 3D ± R was cost-effective compared to NT and SOF/LDV.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Cyclopropanes; Disease Progression; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Interferon-alpha; Lactams, Macrocyclic; Liver Cirrhosis; Liver Neoplasms; Macrocyclic Compounds; Markov Chains; Middle Aged; Polyethylene Glycols; Proline; Quality-Adjusted Life Years; Recombinant Proteins; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; United States; Uracil; Valine

Recurrence of hepatitis C virus (HCV) following liver transplantation (LT) is universal for those with ongoing viraemia and is associated with higher rates of allograft failure and death. However, the optimal timing of HCV treatment for patients awaiting transplant remains unclear.. To evaluate the comparative cost-effectiveness of treating HCV pre-LT vs. post-LT (pre-emptive or after HCV recurrence).. A Markov state-transition model was created to simulate the progression of a cohort of HCV-genotype 1 or 4 cirrhotic patients from the time of transplant listing until death. We then used this model to study the cost-effectiveness of ledipasvir-sofosbuvir (LDV/SOF) with ribavirin for 12 weeks, administered for three separate treatment strategies: (i) pre-LT; (ii) post-LT preemptively prior to HCV recurrence; or (iii) post-LT after HCV recurrence.. In the base-case analysis using a median model for end-stage liver disease (MELD) score <25 at the time of transplant, we found that pre-LT treatment of HCV led to more QALYs for fewer dollars compared to other strategies. Analysis limited to living donor LT recipients revealed that pre-LT treatment was also the most cost-effective strategy. When the analysis was repeated for MELD ≥25, decompensated disease (Child-Pugh class B or C), and hepatocellular carcinoma cases, preemptive post-LT strategy was more cost-effective.. Treatment of HCV prior to liver transplantation appears to be the most cost-effective strategy for patients with a MELD score <25. For patients with a MELD ≥25 or decompensated cirrhosis, preemptive post-liver transplantation treatment before HCV recurrence is the most cost-effective strategy.

Topics: Antiviral Agents; Benzimidazoles; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Disease Progression; Drug Therapy, Combination; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Humans; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Neoplasm Recurrence, Local; Quality-Adjusted Life Years; Ribavirin; Sofosbuvir; United States